Divergent effects of acute and repeated quetiapine treatment on dopamine neuron activity in normal vs. chronic mild stress induced hypodopaminergic states
Open accessAbstract
Clinical evidence supports the use of second-generation dopamine D2 receptor antagonists (D2RAs) as adjunctive therapy or in some cases monotherapy in patients with depression. However, the mechanism for the clinical antidepressant effect of D2RAs remains unclear. Specifically, given accumulating evidence for decreased ventral tegmental area (VTA) dopamine system function in depression, an antidepressant effect of a medication that is expected to further reduce dopamine system activity seems paradoxical. In the present paper we used electrophysiological single unit recordings of identified VTA dopamine neurons to characterize the impact of acute and repeated administration of the D2RA quetiapine at antidepressant doses in non-stressed rats and those exposed to the chronic mild stress (CMS) rodent depression model, the latter modeling the hypodopaminergic state observed in patients with depression. We found that acute quetiapine increased dopamine neuron population activity in non-stressed rats, but not in CMS-exposed rats. Conversely, repeated quetiapine increased VTA dopamine neuron population activity to normal levels in CMS-exposed rats, but had no persisting effects in non-stressed rats. These data suggest that D2RAs may exert their antidepressant actions via differential effects on the dopamine system in a normal vs. hypoactive state. This explanation is supported by prior studies showing that D2RAs differentially impact the dopamine system in animal models of schizophrenia and normal rats; the present results extend this phenomenon to an animal model of depression. These data highlight the importance of studying medications in the context of animal models of psychiatric disorders as well as normal conditions.
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Rats exposed to chronic mild stress have fewer spontaneously active dopamine neurons, an effect more pronounced in females.
“Rats exposed to chronic mild stress have fewer spontaneously active dopamine neurons [52, 53], an effect more pronounced in females [53].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [52]
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Cites
Selective Cortical Undercutting As a Means of Modifying and Studying Frontal Lobe Function in Man
Scoville, W. B. (1949) · Journal of neurosurgery · doi:10.3171/jns.1949.6.1.0065 · Cited by 7,373 · see citing works
Reconsidering anhedonia in depression: Lessons from translational neuroscience
Treadway, M. T., & Zald, D. H. (2011) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2010.06.006 · Cited by 1,579 · see citing works
The control of firing pattern in nigral dopamine neurons: burst firing
Grace, A., & Bunney, B. (1984) · Journal of Neuroscience · doi:10.1523/jneurosci.04-11-02877.1984 · Cited by 1,346 · see citing works
Self-citationDysregulation of the dopamine system in the pathophysiology of schizophrenia and depression
Grace, A. A. (2016) · Nature Reviews Neuroscience · doi:10.1038/nrn.2016.57 · Cited by 1,166 · see citing works
Self-citationDepression, Stress, and Anhedonia: Toward a Synthesis and Integrated Model
Pizzagalli, D. A. (2014) · Annual Review of Clinical Psychology · doi:10.1146/annurev-clinpsy-050212-185606 · Cited by 1,155 · see citing works
Dopamine neurons modulate neural encoding and expression of depression-related behaviour
Tye, K. M., Mirzabekov, J. J., Warden, M. R., Ferenczi, E. A., Tsai, H.-C., Finkelstein, J., Kim, S.-Y., Adhikari, A., Thompson, K. R., Andalman, A. S., et al. (2013) · Nature · doi:10.1038/nature11740 · Cited by 1,073 · see citing works
Regulation of firing of dopaminergic neurons and control of goal-directed behaviors
Grace, A. A., Floresco, S. B., Goto, Y., & Lodge, D. J. (2007) · Trends in Neurosciences · doi:10.1016/j.tins.2007.03.003 · Cited by 1,034 · see citing works
Self-citationNeuroleptics and operant behavior: The anhedonia hypothesis
Wise, R. A. (1982) · Behavioral and Brain Sciences · doi:10.1017/s0140525x00010372 · Cited by 1,022 · see citing works
Grace, A. A., & Bunney, B. S. (1983) · Neuroscience · doi:10.1016/0306-4522(83)90135-5 · Cited by 937 · see citing works
Self-citationRapid effects of deep brain stimulation for treatment-resistant major depression
Schlaepfer, T. E., Bewernick, B. H., Kayser, S., Mädler, B., & Coenen, V. A. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.01.034 · Cited by 563 · see citing works
Acute and chronic haloperidol treatment: Comparison of effects on nigral dopaminergic cell activity
Bunney, B. S., & Grace, A. A. (1978) · Life Sciences · doi:10.1016/0024-3205(78)90471-x · Cited by 553 · see citing works
Self-citationKapur, S., VanderSpek, S. C., Brownlee, B. A., & Nóbrega, J. N. (2003) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.102.046987 · Cited by 480 · see citing works
Are you or aren’t you? Challenges associated with physiologically identifying dopamine neurons
Ungless, M. A., & Grace, A. A. (2012) · Trends in Neurosciences · doi:10.1016/j.tins.2012.02.003 · Cited by 431 · see citing works
Self-citationKapur, S. (2000) · Archives of General Psychiatry · doi:10.1001/archpsyc.57.6.553 · Cited by 396 · see citing works
Dopamine-cell depolarization block as a model for the therapeutic actions of antipsychotic drugs
Grace, A. A., Bunney, B. S., Moore, H. M., & Todd, C. L. (1997) · Trends in Neurosciences · doi:10.1016/s0166-2236(96)10064-3 · Cited by 284 · see citing works
Self-citationAmygdala-Ventral Pallidum Pathway Decreases Dopamine Activity After Chronic Mild Stress in Rats
Chang, C.-H., & Grace, A. A. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.09.020 · Cited by 239 · see citing works
Self-citationBelujon, P., & Grace, A. A. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.04.014 · Cited by 225 · see citing works
Self-citationRegulation of dopamine system responsivity and its adaptive and pathological response to stress
Belujon, P., & Grace, A. A. (2015) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.2014.2516 · Cited by 185 · see citing works
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Komossa, K., Depping, A. M., Gaudchau, A., Kissling, W., & Leucht, S. (2010) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd008121.pub2 · Cited by 168 · see citing works
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Admon, R., Kaiser, R. H., Dillon, D. G., Beltzer, M., Goer, F., Olson, D. P., Vitaliano, G. D., & Pizzagalli, D. A. (2016) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2016.16010111 · Cited by 136 · see citing works
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Lako, I. M., van den Heuvel, E. R., Knegtering, H., Bruggeman, R., & Taxis, K. (2013) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0b013e3182983ffa · Cited by 125 · see citing works
Valenti, O., Cifelli, P., Gill, K. M., & Grace, A. A. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.2808-11.2011 · Cited by 124 · see citing works
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Goldstein, J. M., Litwin, L. C., Sutton, E. B., & Malick, J. B. (1993) · Psychopharmacology · doi:10.1007/bf02244924 · Cited by 114 · see citing works
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Skarsfeldt, T. (1995) · European Journal of Pharmacology · doi:10.1016/0014-2999(95)00260-r · Cited by 57 · see citing works
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Orsetti, M., Canonico, P. L., Dellarole, A., Colella, L., Brisco, F. D., & Ghi, P. (2007) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301291 · Cited by 53 · see citing works
Valenti, O., & Grace, A. A. (2009) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145709990599 · Cited by 44 · see citing works
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Irene, M. L., Edwin, R. V. D. H., Knegtering, H., Bruggeman, R., & Katja, T. (2013) · Journal of Clinical Psychopharmacology · Cited by 44 · see citing works
Chernoloz, O., Mansari, M. E., & Blier, P. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2012.18 · Cited by 39 · see citing works
Kim, D., Weon, K.-Y., Hong, E.-P., Chung, E. K., & Lee, K. (2016) · Chemical and Pharmaceutical Bulletin · doi:10.1248/cpb.c16-00223 · Cited by 19 · see citing works
New Approaches in the Treatment of Bipolar Depression
Saunders, K., & Goodwin, G. M. (2012) · Current topics in behavioral neurosciences · doi:10.1007/7854_2012_209 · Cited by 9 · see citing works
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Fox, M. E., & Lobo, M. K. (2019) · Molecular Psychiatry · doi:10.1038/s41380-019-0415-3 · Cited by 232 · see citing works
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Lee, E. H., & Han, P. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.03.014 · Cited by 40 · see citing works
Uliana, D. L., Zhu, X., Gomes, F. V., & Grace, A. A. (2022) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2022.935320 · Cited by 32 · see citing works
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Hassan, G. M., Kamar, S. A., Rady, H. Y., Abdelrahim, D. S., hay, N. H. A., & Lasheen, N. N. (2024) · PLoS ONE · doi:10.1371/journal.pone.0296187 · Cited by 6 · see citing works
Xu, L., Zhang, J., Yang, H., Cao, C., Fang, R., Liu, P., Luo, S., Wang, B., Zhang, K., & Wang, L. (2024) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2024.1257911 · Cited by 6 · see citing works
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NAcLat-DBS reduces GABAB1R expression of dopamine neurons to correct depressive symptoms in CMS micePreprint
jing, J., Chao, Y., Xia, L., & Hao, F. (2026) · Research Square · doi:10.21203/rs.3.rs-8315922/v1
- Authors
- Moreines, J. L., Owrutsky, Z. L., Gagnon, K. G., & Grace, A. A.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- Moreines, Jared L.
- Venue
- Translational Psychiatry
- Published
- 2017-12-11
- Volume
- 7
- Issue
- 12
- Pages
- 1275-1275
- ISSN
- 2158-3188 (ISSN-L)
- PMC
- PMC5802622
- OpenAlex
- W2773992465
- Cited by
- 17
- References
- 33
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 1 · 2022: 2 · 2021: 2 · 2020: 1 · 2019: 4 · 2017: 1
- FWCI
- 0.21
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Translational Psychiatry (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- D-Scholarship@Pitt (University of Pittsburgh) (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Institutes of Health (5r01mh101180-05)
- National Institute of Mental Health (R01-MH101180, F30MH105199)
- National Institute of General Medical Sciences (T32GM008208)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- quetiapine, dopamine D2 receptor antagonists, depression, chronic mild stress, ventral tegmental area, dopaminergic neurons, hypodopaminergic state, antidepressant mechanism, single-unit recording
- MeSH terms
- Quetiapine Fumarate, Animals, Antidepressive Agents, Depression, Male, Stress, Psychological, Rats, Sprague-Dawley, Ventral Tegmental Area, Dopaminergic Neurons, Dopamine D2 Receptor Antagonists
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